This research was designed to investigate the relationship of immunoregulation to the clinical activity of disease in both human and murine non-Hodgkin's lymphoma and to explore the potential of monitoring treatment in NHL using flow cytometric analysis of peripheral blood mononuclear cells. In human non-Hodgkin's lymphoma, the following has been observed: (1)\There is an inverse relationship between disease activity and the absolute number and percentages of activated T\suppressor cells in both chronic lymphocytic leukemia and the other forms of non-Hodgkin's lymphoma. (2)\In Waldenstrom's macroglobulinemia, there is a functional defect of nonspecific T\suppressor cells in the nonaffected family members. (3)\Peripheral blood involvement by cell surface marker analysis has been found in greater than 95% of patients with all stages of non-Hodgkin's lymphoma by flow cytometric analysis. (4)\Cell cycle analysis has revealed aneuploidy in greater than 80% of the patients studied. (5)\Preliminary data suggest that the involvement of CLL into Richter's Syndrome can be predicted by the use of the monoclonal antibody J5 or CALLA. We have discovered a natural murine model of both nodular and diffuse non-Hodgkin's lymphomas. As in humans, this tumor involves lymph nodes, spleen, bone marrow and peripheral blood. In addition, this tumor has a tendency to progress in activity from the nodular to the diffuse stage using sequential cell surface marker analysis and histopathology of splenic samples. Again, as in humans, we find peripheral blood involvement by flow cytometric cell surface analysis in all of the mice studies to date. Finally, affected mice revealed decrease-activated T\cells which correlate inversely with the activity with disease, mitogen and antigen hyporesponsiveness and complications similar to those in humans such as autoimmune hematolytic anemia and monoclonal gammopathy. Preliminary data suggest that the natural progression of disease in the mice can be interpreted by the injection of purified populations of immunoregulatory cell types from young nonaffected mice. Attempts are now in progress to solidify these data and to use purified factors from these immunoregulatory cell types to control disease activity.